The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations

Thiopurine methyltransferase metabolizes 6-mercaptopurine, thioguanine and azathioprine, thereby regulating cytotoxicity and clinical response to thes e thiopurine drugs, In healthy Caucasian populations, 89-94% of individuals have high thiopurine methyltransferase activity, 6-11% intermediate and 0. 3% low resulting from genetic polymorphism. Four variant thiopurine methylt ransferase alleles were detected in over 80% of individuals with low or int ermediate thiopurine methyltransferase activity. The wild-type allele is de fined as TPMT*1 and the mutant alleles are TPMT*2 (G238C), TPMT*3A (G460A a nd A719G), TPMT*3B (G460A) and TPMT*3C (A719G). The frequency of these alle les in different ethnic groups is not well defined, In this study, DNA from 199 British Caucasian, 99 British South West Asian and 192 Chinese individ uals was analysed for the presence of these variant alleles using polymeras e chain reaction-restriction fragment length polymorphism and allele-specif ic polymerase chain reaction based assays. The frequency of individuals wit h a variant thiopurine methyltransferase genotype was: Caucasians 10.1% (20 /199), South West Asians 2.0% (2/99) and Chinese 4.7% (9/192). Two TPMT*2 h eterozygotes were identified in the Caucasian population, but this allele w as not found in the two Asian populations. TPMT*3A was the only mutant alle le found in the South West Asians (two heterozygotes). This was also the mo st common mutant allele in the Caucasians (16 heterozygotes and one homozyg ote) but was not found in the Chinese. All mutant alleles identified in the Chinese population were TPMT*3C (nine heterozygotes). This allele was foun d at a low frequency in the Caucasians (one heterozygote). This suggests th at A719G is the oldest mutation, with G460A being acquired later to form th e TPMT*3A allele in the Caucasian and South West Asian populations, TPMT*2 appears to be a more recent allele, which has only been detected in Caucasi ans to date. These ethnic differences may be important in the clinical use of thiopurine drugs. Pharmacogenetics 9:37-42 (C) 1999 Lippincott Williams & Wilkins.